Postmortem study of organ-specific toxicity in glioblastoma patients treated with a combination of temozolomide, irinotecan and bevacizumab.

PURPOSE: Systemic chemotherapy including monotherapy with temozolomide (TMZ) or bevacizumab (BEV); two-drug combinations, such as irinotecan (IRI) and BEV, TMZ and BEV and a three-drug combination with TMZ, IRI and BEV (TIB) have been used in treating patients with progressive high-grade gliomas including glioblastoma (GBM). Most patients tolerated these regimens well with known side effects of hypertension, proteinuria, and reversible clinical myelosuppression (CM). However, organ- or system- specific toxicities from chemotherapy agents have never been examined by postmortem study. This is the largest cohort used to address this issue in glioma patients. METHODS: Postmortem tissues (from all major systems and organs) were prospectively collected and examined by standard institution autopsy and neuropathological procedures from 76 subjects, including gliomas (N = 68, 44/M, and 24/F) and brain metastases (N = 8, 5/M, and 3/F) between 2009 and 2019. Standard hematoxylin and eosin (H&E) were performed on all major organs including brain specimens. Electronic microscopic (EM) study was carried out on 14 selected subject's kidney samples per standard EM protocol. Medical records were reviewed with adverse events (AEs) analyzed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. A swimmer plot was utilized to visualize the timelines of patient history by treatment group. The binary logistic regression models were performed to explore any associations between treatment strategies and incident myelosuppression. RESULTS: Twenty-four glioma subjects were treated with TIB [median: 5.5 (range: 1-25) cycles] at tumor recurrence. Exposure to IRI significantly increased the frequency of CM (p = 0.05). No unexpected adverse events clinically, or permanent end-organ damage during postmortem examination was identified in glioma subjects who had received standard or prolonged duration of BEV, TMZ or TIB regimen-based chemotherapies except rare events of bone marrow suppression. The most common causes of death (COD) were tumor progression (63.2%, N = 43) followed by aspiration pneumonia (48.5%, N = 33) in glioma subjects. No COD was attributed to acute toxicity from TIB. The study also demonstrated that postmortem kidney specimen is unsuitable for studying renal ultrastructural pathological changes due to autolysis. CONCLUSION: There is no organ or system toxicity by postmortem examinations among glioma subjects who received BEV, TMZ or TIB regimen-based chemotherapies regardless of durations except for occasional bone marrow suppression and reversible myelosuppression clinically. IRI, but not the extended use of TMZ, significantly increased CM in recurrent glioma patients. COD most commonly resulted from glioma tumor progression with infiltration to brain stem and aspiration pneumonia.

The cell theory and cellular pathology: Discovery, refinements and applications fundamental to advances in biology and medicine.

This review explores the developments leading up to the establishment of the cell theory and cellular pathology and their subsequent refinements and applications while focusing on the individuals who have made seminal advances in the field. The links between cell biology, cell pathology and cell injury research are emphasized. Recognition also is given to the importance of technological advances in microscopy, histology, biochemical and molecular methods for discovery in cell biology and cell pathology. Particular attention is focused on the work of Rudolph Virchow and his former students in the formulation of the cell theory in biology and pathology and John F. R. Kerr and colleagues who identified and developed a comprehensive characterization of apoptosis, thereby giving impetus to the contemporary field of cell injury research. Cell injury research remains an important and fruitful field of ongoing inquiry and discovery.

Granulomatous fungal and non-tuberculous mycobacterial infestation complicating chronic lung disease: Outcomes in patients undergoing lung transplantation.

INTRODUCTION: Granulomatous infections are common in patients with chronic lung disease. We aim to study the incidence and clinicopathological features of granulomatous infections in a cohort of patients undergoing lung transplantation for end-stage chronic lung disease. METHODS: Pathology reports of 50 explanted native lungs of patients who underwent lung transplantation since 2015 at our institution were reviewed. Four cases with granulomatous lesions were identified. Correlation was made with clinical findings in the 4 cases. RESULTS: The granulomatous infections include non-necrotizing cryptococcal pneumonitis (case 1), necrotizing pneumonia due to Scedosporium sp. and Mycobacterium avium Complex (MAC) (Cases 2 and 3), and invasive Aspergillus pneumonia (Case 4). One patient received pre-transplant fungal prophylaxis (Case 4). Post-transplant infectious complications included invasive (Cases 2 and 4) and non-invasive (Case 1) fungal infections and bacterial pneumonia (Cases 1 and 2). Two patients (Cases 3 and 4) developed acute cellular rejection (ACR) in the first 30 days. The third patient (Case 1) was identified with ACR in the 9 months post-transplant and chronic lung allograft dysfunction at 29 months. In terms of mortality, 1 patient (Case 1) died at 30 months post-transplant from pseudomonal sepsis and chronic graft failure. Two patients with invasive fungal infections (Cases 2 and 4) are on secondary prophylaxis and doing well. One patient (Case 3) remains infection-free and on MAC prophylaxis. CONCLUSIONS: In our case series, patients with chronic lung diseases with superimposed granulomatous infestations frequently experienced post-transplant complications. These include invasive infections and repeat ACRs that predispose patients to chronic graft dysfunction. Pre- and post-transplant antifungal prophylaxis reduces fungal load and complication risk post-transplant.

Ulnar Artery Aneurysm as a Late Sequela of Marfan Syndrome.

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations of the FBN1 gene encoding fibrillin-1, which leads to overexpression of transforming growth factor-ß, increased hyaluronan deposition, and matrix metalloproteinase activity in the media of the aorta and other muscular arteries. Marfan syndrome patients present with connective tissue laxity and aneurysmal changes to muscular arteries. Successful medical and surgical intervention has prolonged the life expectancy of MFS patients, which can allow atypical presentations of the syndrome to manifest. We present a case of a 49-year-old man with MFS who developed an ulnar artery aneurysm that was treated by excision and vein grafting.

Cardiac repair and the putative role of stem cells.

Stem cell biology has informed and energized cardiac regenerative medicine. The field is linked to a construct that challenges long-standing concepts and advances the basic tenets that: 1) the mammalian heart has the capacity for significant regeneration of cardiomyocytes (CMC) by reentry of CMC into the cell cycle and by activation of endogenous cardiac stem cells and 2) the administration of exogenous stem cell preparations can result in significant myocardial repair and regeneration in cardiac diseases. Based on the latter, major resources have been invested in clinical trials of stem cell therapy. In this review, the cardiac regenerative construct is critically analyzed. This analysis reconfirms the fundamental pathobiological realities that: 1) the mammalian heart behaves as a terminally differentiated organ with limited regenerative capacity and uncertain contribution from endogenous cardiac stem cells, 2) the healing of infarction is by scar formation, and 3) the progression of pathological myocardial remodeling produces heart failure in non-ischemic as well as ischemic disease. Some influential studies underpinning the cardiac regenerative construct now have been called into question. The efficacy of stem cell therapy to produce sustained beneficial effects in patients with ischemic and non-ischemic heart disease remains unproven. It is an open question as to whether new scientific discovery can provide a convincing rationale for further clinical trials of cardiac stem cell therapy. This should be taken into consideration in regulatory review of ongoing and future clinical trials in cardiac regenerative medicine.

Medical education today: all that glitters is not gold.

BACKGROUND: The medical education system based on principles advocated by Flexner and Osler has produced generations of scientifically grounded and clinically skilled physicians whose collective experiences and contributions have served medicine and patients well. Yet sweeping changes launched around the turn of the millennium have constituted a revolution in medical education. In this article, a critique is presented of the new undergraduate medical education (UME) curricula in relationship to graduate medical education (GME) and clinical practice. DISCUSSION: Medical education has changed and will continue to change in response to scientific advances and societal needs. However, enthusiasm for reform needs to be tempered by a more measured approach to avoid unintended consequences. Movement from novice to master in medicine cannot be rushed. An argument is made for a shoring up of biomedical science in revised curricula with the beneficiaries being nascent practitioners, developing physician-scientists --and the public. CONCLUSION: Unless there is further modification, the new integrated curricula are at risk of produce graduates deficient in the characteristics that have set physicians apart from other healthcare professionals, namely high-level clinical expertise based on a deep grounding in biomedical science and understanding of the pathologic basis of disease. The challenges for education of the best possible physicians are great but the benefits to medicine and society are enormous.

Treatment of Multiple Myeloma in a Heart Transplant Recipient.

Malignancy following solid organ transplant remains a significant threat to the survival of cardiac transplant recipients. Plasma cell dyscrasias including multiple myeloma have been encountered in this population, and medication treatments traditionally used to treat these disorders demonstrate immunomodulatory effects that may have implications on the transplanted allograft. Lenalidomide is an immunomodulatory agent that has been used to treat plasma cell disorders, including light-chain amyloidosis (AL) and multiple myeloma, and represents such a class of medications in which the risks and benefits in the solid organ transplant population remain to be fully elucidated. This report highlights a clinical practice issue where the treatment of a patient's multiple myeloma with lenalidomide may have potentiated an episode of severe acute cellular rejection and further demonstrates the need for future investigation of the optimal treatment of plasma cell disorders including AL amyloidosis and multiple myeloma following solid organ transplantation.

Prevention of perioperative vascular prosthetic infection with a novel triple antimicrobial-bonded arterial graft.

OBJECTIVE: Previously, we investigated a locally developed technique of bonding arterial grafts with three antimicrobials to protect against early (within 2 weeks) perioperative bacterial contamination encountered occasionally during aortic graft prosthetic reconstruction. Vascular graft infections are classified by their appearance time (early [<4 months] vs late [>4 months] after graft implantation), degree of incorporation into the surrounding vessel wall, connectivity to the postoperative wound, and extent of graft involvement. In the current phase of testing, we evaluated the ability of our novel triple antimicrobial-bonded graft to prevent infection in the first 8 weeks after implantation. METHODS: In nine Sinclair miniature pigs, we surgically implanted a 6-mm vascular Dacron patch graft in the infrarenal abdominal aorta. Five pigs received grafts chemically bonded with a 60-mg/mL solution of rifampin, minocycline, and chlorhexidine, and four pigs received unbonded grafts. Before implantation, the five bonded grafts and three of the unbonded grafts were immersed for 15 minutes in a 2-mL solution containing 1-2 × 107 colony-forming units (CFUs)/mL of Staphylococcus aureus (ATCC 29213); the fourth unbonded graft served as a control. RESULTS: At week 9, all of the grafts were explanted. All S aureus-inoculated bonded grafts (n = 5) showed no bacterial growth. The unbonded, uninoculated graft (n = 1) showed low-level bacterial growth (<1.2 × 103 CFUs); S cohnii spp urealyticus, but not S aureus, was isolated, which suggested accidental direct perioperative contamination. Two pigs that received S aureus-inoculated, unbonded grafts were euthanized because of severe S aureus infection (<6.56 × 108 CFUs per graft). Results of histopathologic analysis were concordant with the microbiologic findings. Most intergroup differences were observed in the inflammatory infiltrate in the aortic wall at the site of graft implantation. In all pigs that received bonded grafts, Gram staining showed no bacteria. CONCLUSIONS: Our triple-bonded aortic graft prevented perioperative aortic graft infection for at least 8 weeks in a porcine model. The synergistic antimicrobial activity of this graft was sufficient to prevent and/or eradicate infection during that period. Further studies are needed to assess the graft's ability to combat early-onset vascular graft infection for up to 4 months.

Fibrosis and heart failure.

The extracellular matrix (ECM) is a living network of proteins that maintains the structural integrity of the myocardium and allows the transmission of electrical and mechanical forces between the myocytes for systole and diastole. During ventricular remodeling, as a result of iterations in the hemodynamic workload, collagen, the main component of the ECM, increases and occupies the areas between the myocytes and the vessels. The resultant fibrosis (reparative fibrosis) is initially a compensatory mechanism and may progress adversely influencing tissue stiffness and ventricular function. Replacement fibrosis appears at sites of previous cardiomyocyte necrosis to preserve the structural integrity of the myocardium, but with the subsequent formation of scar tissue and widespread distribution, it has adverse functional consequences. Continued accumulation of collagen impairs diastolic function and compromises systolic mechanics. Nevertheless, the development of fibrosis is a dynamic process wherein myofibroblasts, the principal cellular elements of fibrosis, are not only metabolically active and capable of the production and upregulation of cytokines but also have contractile properties. During the process of reverse remodeling with left ventricular assist device unloading, cellular, structural, and functional improvements are observed in terminal heart failure patients. With the advent of anti-fibrotic pharmacologic therapies, cellular therapy, and ventricular support devices, fibrosis has become an important therapeutic target in heart failure patients. Herein, we review the current concepts of fibrosis as a main component of ventricular remodeling in heart failure patients. Our aim is to integrate the histopathologic process of fibrosis with the neurohormonal, cytochemical, and molecular changes that lead to ventricular remodeling and its physiologic consequences in patients. The concept of fibrosis as living scar allows us to envision targeting this scar as a means of improving ventricular function in heart failure patients.

Acute aortic dissections with pregnancy in women with ACTA2 mutations.

Mutations in ACTA2 predispose to thoracic aortic aneurysms and dissection as well as coronary artery and cerebrovascular disease. Here we examined the risk of aortic dissections, stroke and myocardial infarct with pregnancy in women with ACTA2 mutations. Of the 53 women who had a total of 137 pregnancies, eight had aortic dissections in the third trimester or the postpartum period (6% of pregnancies). One woman also had a myocardial infarct that occurred during pregnancy that was independent of her aortic dissection. Compared to the population-based frequency of peripartum aortic dissections of 0.6%, the rate of peripartum aortic dissections in women with ACTA2 mutations is much higher (8 out of 39; 20%). Six of these dissections initiated in the ascending aorta (Stanford type A), three were fatal. Three women had ascending aortic dissections at diameters less that 5.0 cm (range 3.8-4.7 cm). Aortic pathology showed mild to moderate medial degeneration of the aorta in three women. Of note, five of the women had hypertension either during or before the pregnancy. In summary, the majority of women with ACTA2 mutations did not have aortic or other vascular complications with pregnancy. However, these findings show that pregnancy is associated with significant risk for aortic dissection in women with ACTA2 mutations. Women with ACTA2 mutations who are planning to get pregnant should be counseled about this risk of aortic dissection, and proper clinical management should be initiated to reduce this risk.

A Rare Case of Fabry's Disease-Induced Cardiomyopathy: A Case Report and Review of the Literature.

Fabry's disease, also known as Anderson-Fabry Disease (AFD), is caused by mutations in the α galactosidase A (α GalA) gene found on the X chromosome. This condition results in an accumulation of sphingolipids, including globotriaosylceramide (Gb3), in cells throughout the body. The main effects of Fabry disease typically involve heart, kidney, and nervous system complications. A common cardiac dysfunction is left ventricular hypertrophy. In this case study, we share findings about cardiomyopathy resulting from Fabry disease to explain how this condition impacts the heart and the importance of a biopsy in making a diagnosis. A 57-year-old woman with end-stage renal disease likely attributed to hypertension was evaluated for a kidney transplant. An echocardiogram revealed severe ventricular hypertrophy. The clinical team ordered blood levels of alpha-galactosidase, globotriaosylceramide, and globotriaosylsphingosine enzymes, which demonstrated significant deficiency. Consequently, a genetic test along with an endomyocardial biopsy (EMB) was ordered. Under microscopy using hematoxylin and eosin stain (H/E) and periodic acid Schiff stain (PAS), myocyte vacuolization was observed, which remained unchanged when diastase was added. Electron microscopy revealed inclusion bodies described as myeloid and curvilinear bodies within cells, interstitial cells, and cardiomyocytes. Diagnosing Fabry disease can be challenging, as it may be confused with other medical conditions. Our case study showed how EMB played a role in diagnosing the disease and guiding proper treatment.

Sudden unexpected intrapartum death and left ventricular noncompaction involving the right ventricle.

Left ventricular noncompaction (LVNC), involving mainly the right ventricle, is a rare form of congenital heart disorder characterized by a developmental arrest in myocardial compaction, resulting in a spongy appearance of the myocardium, mainly of the right ventricle, rarely detected in fetuses. We report the case of a female fetus with a gestational age of 41+4 weeks who came to our attention for intrapartum sudden unexpected death, resulting in stillbirth. The ventricular walls, particularly the right ventricular wall, appeared thick, hypertrabeculated and spongy, leading to the diagnosis of LVNC involving mainly the right ventricle. The atrioventricular node and His bundle presented areas of fetal dispersion and resorptive degeneration; islands of conduction tissue were detected in the central fibrous body. Arcuate nucleus of the brainstem showed bilateral severe hypoplasia. The right bundle branch was hypoplastic. The final cause of death was an electrical conduction disfunction in an LVNC involving mainly the right ventricle. To the best of our knowledge, the herein described case is the first reported observation of sudden intrapartum death from LVNC involving mainly the right ventricle well documented post-mortem with cardiac conduction and brainstem studies. Our findings confirm the need of an accurate post-mortem examination including the study of the cardiac conduction system on serial section in every case of sudden unexpected fetal death, although there are no universally recognized guidelines.

A Rare Autopsy Case of Aggressive Combined Hepatocellular-Cholangiocarcinoma in 59-Year-Old Female.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a liver tumor with features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). It consists of intermingled malignant biliary and hepatic tissue and thus a distinct entity, rather than two separate coexisting malignancies. A 59-year-old female with a history of hepatitis C and cirrhosis presented with abdominal pain and altered mental status. She developed hematemesis, and despite extensive interventions, she expired one day after her initial presentation. At autopsy, the liver was diffusely and markedly fibrotic with numerous nodules of varying size with invasion into adjacent vasculature. Microscopic examination of the nodules revealed cHCC-CC with stem cell features, lymphovascular invasion, and tumor emboli scattered throughout the right lung. The patient had end-stage liver disease due to the accumulation of damage and consequent fibrosis. This led to portal hypertension with subsequent massive gastrointestinal bleeding, hemorrhagic shock, and death. cHCC-CC is a rare, aggressive primary liver tumor with a poor prognosis. It can present with a cirrhotomemetic pattern with small nodules that can evade clinical and radiographic detection. Autopsy findings can provide valuable insights into the pathogenesis and clinical course of cHCC-CC, highlight the aggressive nature of the disease, and may inform future diagnostic and therapeutic strategies. Accurate diagnosis of this tumor is important for patient management and prognostication.

Cardiac Mass in a 78-Year-Old Patient With a History of Cancer: Diagnostic and Treatment Challenges.

Primary cardiac angiosarcoma is a rare, aggressive malignancy that commonly metastasizes to various organs. The presenting symptoms are typically nonspecific, so a comprehensive examination is required to confirm the diagnosis promptly. This case report describes the presentation of an older patient with a history of neoplasms. Echocardiography and biopsy were performed, but despite surgical intervention to resect a large right atrial mass, the patient died. A final diagnosis of primary angiosarcoma was made based on the resected specimen.

Insights From the Histopathologic Analysis of Acquired and Genetic Thoracic Aortic Aneurysms and Dissections.

OBJECTIVE: The purpose of this study was to apply contemporary consensus criteria developed by the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology to the evaluation of aortic pathology, with the expectation that the additional pathologic information may enhance the understanding and management of aortic diseases. METHODS: A scoring system was applied to ascending aortic specimens from 42 patients with heritable thoracic aortic disease and known genetic variations and from 86 patients from a single year, including patients with known genetic variations (n = 12) and patients with sporadic disease (n = 74). RESULTS: The various types of lesions of medial degeneration and the overall severity of medial degeneration overlapped considerably between those patients with heritable disease and those with sporadic disease; however, patients with heritable thoracic aortic disease had significantly more overall medial degeneration (P = .004) and higher levels of elastic fiber fragmentation (P = .03) and mucoid extracellular matrix accumulation (P = .04) than patients with sporadic thoracic aortic disease. Heritable thoracic aortic disease with known genetic variation was more prevalent in women than in men (27.2% vs 9.8%; P = .04), and women had more severe medial degeneration than men (P = .04). Medial degeneration scores were significantly lower for patients with bicuspid aortic valves than for patients with tricuspid aortic valves (P = .03). CONCLUSION: The study's findings indicate considerable overlap in the pattern, extent, and severity of medial degeneration between sporadic and hereditary types of thoracic aortic disease. This finding suggests that histopathologic medial degeneration represents the final common outcome of diverse pathogenetic factors and mechanisms.

Xenotransplantation of human unrestricted somatic stem cells in a pig model of acute myocardial infarction.

BACKGROUND: Stem cell therapy may help restore cardiac function after acute myocardial infarction (AMI), but the optimal therapeutic cell type has not been identified. METHODS: We examined the effects of CD34-/CD45- human unrestricted somatic stem cells (USSCs) in pigs (n = 30) with an AMI created by a 90-min occlusion of the left anterior descending coronary artery. Pigs were randomly assigned to receive either USSCs (302 ± 23 × 10(6) cells) or phosphate-buffered saline via 15 NOGA-guided transendocardial injections 10 days after AMI. Cyclosporine A (10 mg/kg orally, twice a day) was started in all pigs 3 days before control or cell treatment. Cardiac function was assessed by echocardiography before injection and at 4 and 8 weeks after treatment. Serum titers for pig IgG antibodies against USSCs were also measured at these time points and before AMI. RESULTS: Compared with control pigs, USSC-treated pigs showed no significant differences in any of the functional parameters examined. USSC-treated pigs showed variable increases in anti-USSC IgG antibody titers in the blood and chronic inflammatory infiltrates at the cell injection sites. Immunohistochemical studies of the injection sites using human anti-mitochondrial antibodies failed to detect implanted USSCs. CONCLUSIONS: We conclude that human USSCs did not improve cardiac function in a pig model of AMI. Cell transplantation in a xenogeneic setting may obscure the benefits of stem cell therapy.

A model for cardiomyocyte cell death: insights into mechanisms of oncosis.

It is now known that there are at least two basic patterns of cell injury progressing to cell death: cell injury with swelling, known as oncosis, and cell injury with shrinkage, known as apoptosis. Both types of cell death are "programmed" in the sense that the genetic information and many of the enzymes and other factors pre-exist in the cell. Previous investigation has pointed to cardiomyocyte ischemic injury evolving as the oncotic pattern of injury, although apoptosis has also been implicated. This study was designed, using a unique cell model system, to gain insight into the molecular events of anticancer agent-induced cardiomyocyte injury. Cardiomyocytes exposed for 2 h to 1.5 µg/ml sanguinarine consistently displayed the morphology of apoptosis in over 80% of cells, whereas a higher dose of 25 µg/ml at 2 h yielded the pattern of oncosis in over 90% of cells. Microarray analysis revealed altered expression of 2514 probes in sanguinarine-induced oncosis and 1643 probes in apoptosis at a level of significance of p<0.001. Some of the inductions such as perforin were found to be higher than 11-fold in oncosis. When perforin was blocked by perforin-specific siRNA we found a reduction in oncotic cell death. These results strengthen the notion that oncosis is not representative of nonspecific necrosis, but constitutes a genetically controlled form of "programmed cell death"; and also that oncosis might represent a pathogenetic mechanism of cardiomyocyte injury. This is also the first demonstration of the involvement of perforin in cardiomyocyte oncosis.

Pathobiology of Myocardial Ischemia and Reperfusion Injury: Models, Modes, Molecular Mechanisms, Modulation, and Clinical Applications.

This review presents an integrated approach to the analysis of myocardial ischemia and reperfusion injury and the modulating influence of myocardial conditioning during the evolution of acute myocardial infarction (AMI) and other clinical settings. Experimental studies have involved a spectrum of in vitro, ex vivo, and in vivo models, and guidelines have been developed for the conduct of rigorous preclinical studies and for the identification of various forms of cell injury and death in evolving AMI. AMI in vivo is dominated by oncosis (cell injury with swelling) leading to necroptosis and final necrosis of ischemic cardiomyocytes (CMCs), without or with contraction band formation. Early after coronary occlusion, reperfusion salvages a significant amount of ischemic myocardium in the subepicardium while reperfusion injury contributes up to 50% of the final subendocardial infarct. AMI progression is mediated by damage (or danger)-associated molecular patterns, also known as alarmins, which activate pattern recognition receptors and initiate the inflammatory response. In preclinical studies, lethal reperfusion injury can largely be prevented with preconditioning or postconditioning by pharmacologic or physical means due to effects on both the CMC and microvasculature. Conditioning involves triggers, cytosolic mediators, and intracellular effectors. Mitochondria have a central role in the maintenance and loss of viability of CMCs. Reperfusion of severely ischemic myocardium leads to sustained opening of the mitochondrial permeability transition pore (MPTP). Once the MPTP is opened, the mitochondrial membrane potential (ΔΨm) is rapidly lost and energy production ceases. Conditioning blocks the sustained opening of the MPTP. Translation of conditioning strategies to the clinical management of patients has been challenging. The status of translation of experimental findings to approaches to modulate and ameliorate ischemic and reperfusion injury is discussed for the clinical settings of acute coronary syndromes treated with percutaneous interventions and cardiac preservation during open heart surgery and cardiac transplantation.

Pericentrin deficiency in smooth muscle cells augments atherosclerosis through HSF1-driven cholesterol biosynthesis and PERK activation.

Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is caused by biallelic loss-of-function variants in pericentrin (PCNT), and premature coronary artery disease (CAD) is a complication of the syndrome. Histopathology of coronary arteries from patients with MOPDII who died of CAD in their 20s showed extensive atherosclerosis. Hyperlipidemic mice with smooth muscle cell-specific (SMC-specific) Pcnt deficiency (PcntSMC-/-) exhibited significantly greater atherosclerotic plaque burden compared with similarly treated littermate controls despite similar serum lipid levels. Loss of PCNT in SMCs induced activation of heat shock factor 1 (HSF1) and consequently upregulated the expression and activity of HMG-CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthesis. The increased cholesterol biosynthesis in PcntSMC-/- SMCs augmented PERK signaling and phenotypic modulation compared with control SMCs. Treatment with the HMGCR inhibitor, pravastatin, blocked the augmented SMC modulation and reduced plaque burden in hyperlipidemic PcntSMC-/- mice to that of control mice. These data support the notion that Pcnt deficiency activates cellular stress to increase SMC modulation and plaque burden, and targeting this pathway with statins in patients with MOPDII has the potential to reduce CAD in these individuals. The molecular mechanism uncovered further emphasizes SMC cytosolic stress and HSF1 activation as a pathway driving atherosclerotic plaque formation independently of cholesterol levels.